Proteins required for maintenance of biological functions such as enzymes and receptors have properties called “substrate specificity”, and such proteins are classified into “Lock&Key” type wherein an active site constantly remains unchanged to details of structure of substrate molecule, and “Induced-Fit” (induced-bonding) type wherein an active site is in a random inactive state in the absence of a substrate, and the active site changes into an active state in the presence of a substrate for capturing the coming substrate. By the term induced-fit type, such a receptor is contemplated that the 3D structure of a ligand binding site changes in binding with a ligand to allow intake of the ligand.
As a computational chemical technique for screening for ligand molecules using a 3D structure of a protein, 3D compound database screening (Virtual Screening) as reported in AutoDocK (“Morris, G. M. Goodsell, D. S. Halliday, R. S. Huey, R. Hart, W. E. Belew, R. K. Olson, A. J. (1998) Automated docking using a Lamarckian genetic algorithm and an empirical biding free energy function. J. Comput. Chem. 19:1639-1662; Goodsell, D. S. Morris, G. M. Olson, A. J. (1996) Automated docking of flexible ligands: applications of AutoDock. J. Mol. Recognit, 9: 1-5”), DOCK (“Ewing, T. J. I Makino, S. Skillman, A. G. Kuntz I. D. (2001) DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J. Comput. Aided Mol. Des. 15: 411-28”), FlexX (“Rarey, M, Kramer, B, Lengauer, T, Klebe G. (1996) A fast flexible docking method using an incremental construction algorithm. J. Mol. Biol. 261: 470-89; Rarey, M. Wefing, S. Lengauer, T. (1996) Placement of medium-sized molecular fragments into active sites of proteins. J. Comput. Aided Mol. Des. 10: 41-54”), GOLD (“Jones, G. Willett, P. Glen, R. C. (1995) Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J. Mol. Biol. 245:43-53; Jones, G. Willett, P. Glen, R. C, Leach, A. R. Taylor, R. (1997) Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol. 267: 727-48”), ADAM&EVE (“Mizutani, M. Y. Itai, A. (2004) Efficient method for high-throughput virtual screening based on flexible docking: discovery of novel acetylcholinesterase inhibitors. J. Med. Chem. 47: 4818-4828”) are known. These are also called “High-performance docking study” and enable a mass-scale compound library screening. However, the ability of these techniques to predict binding conformation and binding energy is poor because rough approximation is used for evaluation. In addition, since they fail to consider computational expression parameters corresponding to “induced-binding” which is very important for binding between a protein and a ligand, and even if such consideration is made, it is to such an extent that random numbers are generated and side chains of receptor are moved, and accuracy of the computation result is not sufficient.
As a method for simulating “induced-binding” which is important for binding between protein and ligand, MD (molecular dynamic calculation), MM (molecular mechanical calculation), and MC (Monte Carlo method) are known. These methods provide relatively high accuracy, and enable prediction of binding conformation and binding energy. Here, the technique called “molecular dynamic method (MD)” calculates dynamic structure of a molecule by sequentially solving dynamic equation based on the classical dynamics for each atom constituting the molecule, and enables the simulation of dynamic behavior of a protein with high accuracy. However, it is not necessarily a useful means because it requires significant time for calculation and has difficulty in handling many molecules. Further, molecular dynamic calculation executed for a target protein according to such a conventional method results in a protein 3D structure whose coordinates are largely different from those analyzed by X-ray, NMR and the like. Although such a difference includes a physicochemical description of dynamic behavior of a protein, it sometimes behaves contradictorily to an experimental result of dynamic behavior proved by NMR or the like, and hence it often fails to provide an accurate simulation result.
As described above, in respect of the conventional “in silico screening”, since computational expression parameters corresponding to “induced-binding” which is very important for binding between protein and ligand are not sufficiently considered, it does not deem that the accuracy of the calculation result is adequate.
On the other hand, in molecular simulation, it is possible to express and analyze the above induced-binding; however, significant time is required for obtaining an accurate result. Many results will be influenced by the initial structure coordinates.
Inventors of the present invention examined the way of screening for a ligand that will bind to a target protein when the 3D structure of a certain protein is given. As described above, some currently available receptor-ligand binding analyzing software takes flexibility of a ligand into account, but most of such software fails to consider flexibility of a receptor. Even though there is software that considers flexibility of a receptor, such consideration just moves a side chain of the receptor by generation of random numbers, and most of the software are dedicated to a Lock&Key type receptor. In such circumstances, we attempted to develop receptor-ligand binding analyzing software dedicated to an Induced-Fit type receptor.
The problem to be solved by the present invention is to provide a ligand screening apparatus, a ligand screening method, a program and a recording medium capable of screening for a ligand that binds to a certain protein which is a particularly important key to development of agricultural chemicals and pharmaceuticals and the like, with significantly higher efficiency and accuracy than conventional methods. It is also an object to provide a ligand screening apparatus, a ligand screening method, a program and a recording medium which carry out various modifications of ligand molecules and modifications of proteins such as receptors rapidly and effectively. It is also an object of the present invention to clarify a mode of interaction between a ligand and a protein and make the recognition mechanism of the interaction clear, thereby identifying a cause of disease, and promoting development of related drugs.